Pyridopyrazinones derivatives insulin secretion stimulators, methods for obtaining them and use thereof for the treatment of diabetes

ABSTRACT

The present invention relates to pyridopyrazinone derivatives of formula (I), wherein X, Y, Z1 W, A and R1 are as defined in claim  1 , as insulin secretion stimulators. The invention also relates to the preparation and use of these pyridopyrazinone derivatives for the prophylaxis and/or treatment of diabetes and pathologies associated.

FIELD OF THE INVENTION

The present invention relates to pyridopyrazinone derivatives of formula(I) as insulin secretion stimulators. The invention also relates to thepreparation and use of these pyridopyrazinone derivatives for theprophylaxis and/or treatment of diabetes and pathologies associated.

BACKGROUND OF THE INVENTION

Type 2 diabetes mellitus is one of the most common worldwide diseases.In 2007, its prevalence was estimated at 5.9% (246 million people) ofthe adult population and is in continuous increase. This disease is evenmore serious since it could lead to severe micro- andmacro-complications, which could become disabling or lethal, as diabetesis a major risk factor for cardiovascular disease and stroke.

Type 2 diabetes is characterized by a fasted and post-prandialhyperglycemia, consequence of two main defects: an insulin resistance atthe level of target tissues and an altered insulin secretion from thepancreatic beta cells. This latter anomaly seems to appear very early asit is present at the Impaired Glucose Tolerance (IGT) stage (Mitrakou etal., N. Engl. J. Med. 326: 22-29, 1992). It has been observed in UKProspective Diabetes Study (UKPDS) that 50% of the beta cell function isalready lost when diabetes is diagnosed, suggesting that deteriorationin beta cell function may begin 10-12 years before diabetes diagnosis(Holman, Diabetes Res. CM, Pract. 40 S21, 1998 or UKPDS Group, Diabetes44: 1249-58, 1995).

The defective insulin secretion is due to a quantitative and aqualitative defect of the beta cell, i.e. a decreased beta cell mass anda specific defect of insulin release in response to glucose, especiallythe first phase of secretion, since the response to non-glucosesecretagogues is preserved (Pfeifer et al., Am. J. Med. 70: 579-88,1981). The importance of restoring a normal profile of insulin releasein response to glucose to maintain the glycemic control within a normalrange was supported by studies in non diabetic volunteers showing thatdelaying the first phase of insulin secretion in response to glucose ledto glucose intolerance (Calles-Escandon et al., Diabetes 36: 1167-72,1987).

Oral antidiabetics available for treatment of type 2 diabetic patients,such as sulfonylureas or glinides, are known to induce insulinsecretion, by binding to sulfonyurea receptor on the K-ATP channels ofthe beta cell, leading to increase in intracellular calcium and insulinexocytosis. This insulin release is thus totally independent of theplasma glucose level and treatment with these molecules usually inducessustained hyperinsulinemia, which could lead to several side-effects,such as severe hypoglycaemia, body weight gain, and aggravation ofcardiovascular risk. In addition, the prolonged hyperinsulinemiaobserved with sulfonylurea treatment, with no preservative effect of thebeta cell mass, could lead to secondary failure due to beta cellexhaustion, another deleterious side effect of these compounds.

New treatment of type 2 diabetes should restore a normal profile ofinsulin release specifically in response to glucose, while preserving orincreasing the beta cell mass. This is observed with GLP-1 analogs, suchas exenatide or liraglutide, but these molecules are peptides and mustbe administered by parenteral route.

Such characteristics for a new oral small molecule would be a greatadvantage over the other antidiabetic drugs.

According to the present invention, the compounds of the formula (I) areinsulin secretion stimulators, useful for treatment of diabetes andpathologies associated. They lower blood glucose levels by restoring thedefective glucose-induced insulin secretion in type 2 diabetics.

The patent application WO 2007020521 discloses pyridopyrazinonederivatives as PDE V inhibitors.

EP 770079 discloses pyridopyrazinone derivatives as PDE IV and TNFinhibitors.

The patent application WO 2004031189 discloses pyridopyrazinonederivatives as corticotrophin releasing factor receptor antagonists, fortreatment of anxiety and depression.

U.S. Pat. No. 4,296,114 describes pyridopyrazinone derivatives asantiinflammatory agents.

None of the prior art discloses pyridopyrazinone derivatives withantidiabetic activity.

SUMMARY OF THE INVENTION

The present invention is directed towards pyridopyrazinone derivativesof formula (I). Said derivatives are useful for treating diabetes andpathologies associated therewith. Pyridopyrazinone derivatives accordingto the invention have the following formula (I):

wherein:one atom among X, Y, Z, W is a nitrogen atom and the others are a carbonatom substituted by a substituent selected from:hydrogen,

T;

X is preferably N;

A is:

aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, aryloxyalkyl,arylalkoxy alkyl, arylthioalkyl, arylalkylthioalkyl, heteroarylalkyl,heteroaryloxyalkyl, heteroarylalkoxyalkyl, heteroarylthioalkyl,heteroarylalkylthioalkyl, heterocycloalkylalkyl,heterocycloalkyloxyalkyl, heterocycloalkylalkoxyalkyl,heterocycloalkylthioalkyl, heterocycloalkylalkylthioalkyl, arylakenyl,arylalkynyl; heteroaryl or heterocycloalkyl groups can include one ormore heteroatom selected from N, O and S;each of these groups can be optionally substituted by one or moresubstituents selected from T;preferably, A is:aryl, arylalkyl, heteroaryl which can include one or more heteroatomsselected from N, O and S; each of these groups can be optionallysubstituted by one or more substituents selected from T;more preferably, A is:phenyl, benzyl, each of these groups can be optionally substituted byone or more substituents selected from T;A is preferably aryl, more preferably phenyl;

R1 is:

alkyl, alkyloxyalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl,heterocycloalkyloxyalkyl, heterocycloalkylalkoxyalkyl,heterocycloalkylthioalkyl, heterocycloalkylalkylthloalkyl, R3R4N-alkyl,aryl, heteroaryl, arylalkyl, heteroarylalkyl;each of these groups can be optionally substituted by one or moresubstituents selected from T;preferably, R1 is:alkyl, alkyloxyalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl,heterocycloalkyloxyalkyl, heterocycloalkylalkoxyalkyl,heterocycloalkylthioalkyl, heterocycloalkylalkylthioalkyl, each of thesegroups can be optionally substituted by one or more substituentsselected from T;more preferably, R1 is:is alkyl, alkyloxyalkyl, cycloalkyl, cycloalkylalkyl; each of thesegroups can be optionally substituted by one or more substituentsselected from T; still more preferably, R1 is:ethyl; isopropyl; butyl; 2,2-difluoroethyl; 2-methoxyethyl; cyclopropyl;cyclopropylmethyl;T is chosen without preference from the following groups:hydroxy, thio, halogen, cyano, trifluoromethoxy, trifluoromethyl,carboxy, carboxy methyle, carboxyethyle, alkyle, cycloalkyl, alkoxy,alkylamino, aryle, aryle sulfonylalkyl, aryloxy, arylalkoxy, NR3R4,azido, nitro, guanidino, amidino, phosphono, oxo, carbamoyle,alkylsulfonyl, alkylsulfinyl, alkylthio, SF5, two T groups can form amethylenedioxy;preferably, T is:hydroxy, thio, halogen, cyano, trifluoromethoxy, trifluoromethyl,carboxy, carboxy methyle, carboxyethyle, alkyle, cycloalkyl, alkoxy,aryle, aryle sulfonylalkyl, aryloxy, arylalkoxy, NR3R4, azido,guanidino, amidine, phosphono, oxo, carbamoyle, alkylsulfonyl,alkylsulfinyl, alkylthio, SF5, two T groups can form a methylenedioxy;more preferably, T is:halogen, trifluoromethyl, alkyle, alkoxy;still more preferably, T is:alkyl, cycloalkyl, Cl, F;R3 and R4 are independently selected from:hydrogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl;R3 and R4 can also constitute an heterocycloakyl group which can includeone or more heteroatoms selected from N, O and S;R3 and R4 independently can be optionally substituted by one or moresubstituents selected from T;preferably, R3 and R4 are independently selected from lower alkyl,cycloalkyl;as well as its racemic forms, tautomers, enantiomers, diastereomers,epimers and polymorphs, and mixtures thereof, and the pharmaceuticallyacceptable salts thereof.

The compounds of the formula (I) may be chosen from:

-   1-cyclopropyl-3-(4-fluorophenyl)pyrido[3,4-b]pyrazin-2(1H)-one-   1-cyclopropyl-3-[4-(trifluoromethyl)phenyl]pyrido[3,4-b]pyrazin-2(1H)-one-   1-cyclopropyl-3-phenylpyrido[3,4-b]pyrazin-2(1H)-one-   2-(3-chlorophenyl)-4-cyclopropylpyrido[2,3-b]pyrazin-3(4H)-one-   2-(4-chloro-2-methylphenyl)-4-cyclopropylpyrido[2,3-b]pyrazin-3(4H)-one-   2-(4-chlorobenzyl)-4-cyclopropylpyrido[2,3-b]pyrazin-3(4H)-one-   2-(4-chlorophenyl)-4-(2,2-difluoroethyl)pyrido[2,3-b]pyrazin-3(4H)-one-   2-(4-chlorophenyl)-4-(2-methoxyethyl)pyrido[2,3-b]pyrazin-3(4H)-one-   2-(4-chlorophenyl)-4-cyclopropyl-6-methylpyrido[2,3-b]pyrazin-3(4H)-one-   2-(4-chlorophenyl)-4-cyclopropyl-7-methylpyrido[2,3-b]pyrazin-3(4H)-one-   2-(4-chlorophenyl)-4-cyclopropyl-8-methylpyrido[2,3-b]pyrazin-3(4H)-one-   2-(4-chlorophenyl)-4-cyclopropylmethylpyrido[2,3-b]pyrazin-3(4H)-one-   2-(4-chlorophenyl)-4-cyclopropylpyrido[2,3-b]pyrazin-3(4H)-one-   2-(4-chlorophenyl)-4-ethylpyrido[2,3-b]pyrazin-3(4H)-one-   2-(4-chlorophenyl)-4-isopropyl-pyrido[2,3-b]pyrazin-3(4H)-one-   2-(4-fluorophenyl)-4-(2-methoxyethyl)pyrido[2,3-b]pyrazin-3(4H)-one-   2-(4-fluorophenyl)-4-ethylpyrido[2,3-b]pyrazin-3(4H)-one-   2-(4-fluorophenyl)-4-isopropyl-pyrido[2,3-b]pyrazin-3(4H)-one-   3-(4-chlorophenyl)-1-cyclopropylpyrido[3,4-b]pyrazin-2(1H)-one-   4-(2,2-difluoroethyl)-2-(4-fluorophenyl)pyrido[2,3-b]pyrazin-3(4H)-one-   4-(2,2-difluoroethyl)-2-(4-trifluoromethylphenyl)pyrido[2,3-b]pyrazin-3(4H)-one-   4-(2,2-difluoroethyl)-2-phehylpyrido[2,3-b]pyrazin-3(4H)-one-   4-(2-methoxyethyl)-2-(4-trifluoromethylphenyl)-pyrido[2,3-b]pyrazin-3(4H)-one-   4-(2-methoxyethyl)-2-phenylpyrido[2,3-b]pyrazin-3(4H)-one-   4-(cyclopropylmethyl)-2-(4-fluoro-2-methylphenyl)pyrido[2,3-b]pyrazin-3(4H)-one-   4-butyl-2-(4-chlorophenyl)-pyrido[2,3-b]pyrazin-3(4H)-one-   4-cyclobutyl-2-(4-fluorophenyl)pyrido[2,3-]pyrazin-3(4H)-one-   4-cyclopropyl-2-(3-fluorophenyl)-pyrido[2,3-b]pyrazin-3(4H)-one-   4-cyclopropyl-2-(3-methylphenyl)pyrido[2,3-b]pyrazin-3(4H)-one-   4-cyclopropyl-2-(4-fluoro-2-methylphenyl)pyrido[2,3-b]pyrazin-3(4H)-one-   4-cyclopropyl-2-(4-fluoro-2-methylphenyl)pyrido[2,3-b]pyrazin-3(4H)-one-   4-cyclopropyl-2-(4-fluorophenyl)-6-methoxypyrido[2,3-b]pyrazin-3(4H)-one-   4-cyclopropyl-2-(4-fluorophenyl)-6-methylpyrido[2,3-b]pyrazin-3(4H)-one-   4-cyclopropyl-2-(4-fluorophenyl)-7-methylpyrido[2,3-b]pyrazin-3(4H)-one-   4-cyclopropyl-2-(4-fluorophenyl)-8-methylpyrido[2,3-b]pyrazin-3(4H)-one-   4-cyclopropyl-2-(4-fluorophenyl)pyrido[2,3-b]pyrazin-3(4H)-one-   4-cyclopropyl-2-(4-methylphenyl)pyrido[2,3-b]pyrazin-3(4H)-one-   4-cyclopropyl-2-(4-trifluoromethylphenyl)-8-methylpyrido[2,3-b]pyrazin-3(4H)-one-   4-cyclopropyl-2-(4-trifluoromethylphenyl)-8-methylpyrido[2,3-b]pyrazin-3(4H)-one-   CL    4-cyclopropyl-2-(4-trifluoromethylphenyl)-pyrido[2,3-b]pyrazin-3(4H)-one-   4-cyclopropyl-2-[3-(trifluoromethyl)phenyl]pyrido[2,3-b]pyrazin-3(4H)-one-   4-cyclopropyl-2-phenylpyrido[2,3-b]pyrazin-3(4H)-one-   4-cyclopropylmethyl-2-(4-fluoro-2-methylphenyl)-pyrido[2,3-b]pyrazin-3(4H)-one-   4-cyclopropylmethyl-2-(4-fluorophenyl)pyrido[2,3-b]pyrazin-3(4H)-one-   4-cyclopropylmethyl-2-(4-trifluoromethylphenyl)pyrido[2,3-b]pyrazin-3(4H)-one-   4-cyclopropylmethyl-2-phenylpyrido[2,3-b]pyrazin-3(4H)-one-   4-ethyl-2-phenylpyrido[2,3-b]pyrazin-3(4H)-one-   4-isopropyl-2-phenylpyrido[2,3-b]pyrazin-3(4H)-one,-   2-(2-Chlorophenyl)-4-cyclopropylpyrido[2,3-b]pyrazin-3(4H)-one-   4-Cyclopropyl-2-(2,4-dichlorophenyl)pyrido[2,3-b]pyrazin-3(4H)-one-   4-Cyclopropyl-2-(2,4,5-trifluorophenyl)pyrido[2,3-b]pyrazin-3(4H)-one-   4-Cyclopropyl-2-(2-methoxyphenyl)pyrido[2,3-b]pyrazin-3(4H)-one-   4-Cyclopropyl-2-(4-methoxyphenyl)pyrido[2,3-b]pyrazin-3(4H)-one-   2-(4-Chloro-2-methylphenyl)-4-isopropylpyrido[2,3-b]pyrazin-3(4H)-one-   2-(2,4-Dichlorophenyl)-4-isopropylpyrido[2,3-b]pyrazin-3(4H)-one-   2-(4-Fluoro-2-methylphenyl)-4-isopropylpyrido[2,3-b]pyrazin-3(4H)-one-   2-(2-Ethoxyphenyl)-4-isopropylpyrido[2,3-b]pyrazin-3(4H)-one-   4-cyclopropyl-2-(6-methoxypyridin-3-yl)pyrido[2,3-b]pyrazin-3(4H)-one-   4-cyclopropyl-2-(2-thienyl)pyrido[2,3-b]pyrazin-3(4H)-one-   4-cyclopropyl-2-(2-furyl)pyrido[2,3-b]pyrazin-3(4H)-one-   2-(4-Chlorophenyl)-4-(2-hydroxyethyl)pyrido[2,3-b]pyrazin-3(4H)-one-   2-(4-Fluorophenyl)-4-(2-hydroxyethyl)pyrido[2,3-b]pyrazin-3(4H)-one-   4-(2-hydroxyethyl)-2-phenylpyrido[2,3-b]pyrazin-3(4H)-one-   2-(4-Chlorophenyl)-4-(3-hydroxypropyl)pyrido[2,3-b]pyrazin-3(4H)-one-   2-(4-Fluorophenyl)-4-(3-hydroxypropyl)pyrido[2,3-b]pyrazin-3(4H)-one-   4-(3-Hydroxypropyl)-2-phenylpyrido[2,3-b]pyrazin-3(4H)-one-   2-(4-chloro-2-methylphenyl)-4-(2-hydroxyethyl)pyrido[2,3-b]pyrazin-3(4H)-one-   2-(4-fluoro-2-methylphenyl)-4-(2-hydroxyethyl)pyrido[2,3-b]pyrazin-3(4H)-one-   2-(4-chloro-2-methylphenyl)-4-(2-methoxyethyl)pyrido[2,3-b]pyrazin-3(4H)-one-   2-(4-fluoro-2-methylphenyl)-4-(2-methoxyethyl)pyrido[2,3-b]pyrazin-3(4H)-one-   4-cyclopropyl-2-(2,4-dimethylphenyl)pyrido[2,3-b]pyrazin-3(4H)-one-   2-(4-chlorophenyl)-4-[2-(diethylamino)ethyl]pyrido[2,3-b]pyrazin-3(4H)-one-   2-(4-chlorophenyl)-4-[2-(diethylamino)ethyl]pyrido[2,3-b]pyrazin-3(4H)-one-   1-ethyl-3-(4-fluorophenyl)pyrido[2,3-b]pyrazin-2(1H)-one    as well as its racemic forms, tautomers, enantiomers, diastereomers,    epimers and polymorphs, and mixtures thereof, and the    pharmaceutically acceptable salts thereof.

More preferably, the compounds of the formula (I) according to theinvention may be chosen from:

-   2-(4-chlorobenzyl)-4-cyclopropylpyrido[2,3-b]pyrazin-3(4H)-one-   2-(4-chlorophenyl)-4-(2,2-difluoroethyl)pyrido[2,3-b]pyrazin-3(4H)-one-   2-(4-chlorophenyl)-4-(cyclopropylmethyl)pyrido[2,3-b]pyrazin-3(4H)-one-   2-(4-chlorophenyl)-4-cyclopropylmethylpyrido[2,3-b]pyrazin-3(4H)-one-   2-(4-chlorophenyl)-4-cyclopropylpyrido[2,3-b]pyrazin-3(4H)-one-   2-(4-chlorophenyl)-4-ethylpyrido[2,3-b]pyrazin-3(4H)-one-   2-(4-chlorophenyl)-4-isopropyl-pyrido[2,3-b]pyrazin-3(4H)-one-   2-(4-fluorophenyl)-4-(2-methoxyethyl)pyrido[2,3-b]pyrazin-3(4H)-one-   2-(4-fluorophenyl)-4-(2-methoxyethylpyrido[2,3-b]pyrazin-3(4H)-one-   2-(4-fluorophenyl)-4-ethylpyrido[2,3-b]pyrazin-3(4H)-one-   2-(4-Fluorophenyl)-4-(2-hydroxyethyl)pyrido[2,3-b]pyrazin-3(4H)-one-   4-cyclopropyl-2-(4-fluorophenyl)pyrido[2,3-b]pyrazin-3(4H)-one-   4-cyclopropyl-2-ethylpyrido[2,3-b]pyrazin-3(4H)-one-   4-cyclopropylmethyl-2-(4-fluorophenyl)pyrido[2,3-b]pyrazin-3(4H)-one-   4-ethyl-2-phenylpyrido[2,3-b]pyrazin-3(4H)-one    as well as its racemic forms, tautomers, enantiomers, diastereomers,    epimers and polymorphs, and mixtures thereof, and the    pharmaceutically acceptable salts thereof.

The invention also relates to the racemic forms, tautomeric forms,enantiomers, diastereoisomers, epimers and organic or mineral salts ofthe compounds of the general formula (I), as well as their crystallineforms, including their polymorphic forms and the polymorphic forms ofthe compounds of formula (I).

The present invention is directed not only to racemic mixtures of thesecompounds, but also to individual stereoisomers and/or diastereoisomersthereof as well or as mixtures of these in all proportions.

The compounds of the invention of the formula (I), as defined above,containing a sufficiently acidic function or a sufficiently basicfunction, or both, may include the corresponding pharmaceuticallyacceptable salts of an organic or mineral add or of an organic ormineral base.

The expression “pharmaceutically acceptable salts” refers to therelatively nontoxic mineral and organic acid-addition salts, and thebase-addition salts, of the compounds of the present invention. Thesesalts may be prepared in situ during the final isolation andpurification of the compounds.

In particular, the acid-addition salts may be prepared by separatelyreacting the purified compound in its purified form with an organic ormineral acid and isolating the salt thus formed. The resulting saltsare, for example, hydrochlorides, hydrobromides, sulfates,hydrogenosulfates, dihydrogenophosphates, citrates, maleates, fumarates,trifluoroacetates, 2-naphtalenesulfonates, para-toluenesulfonates.

The invention also relates to pharmaceutically acceptable salts withorganic or inorganic bases. In particular, the basic-addition salts maybe prepared by separately reacting the purified compound in its purifiedform with an organic or inorganic base and isolating the salt thusformed. The resulting salts are, for example, metal salts, particularlyalkali metal salts, alkaline-earth metal salts and transition metalsalts (such as sodium, potassium, calcium, magnesium, aluminum), orsalts obtained with bases, such as ammonia or secondary or tertiaryamines (such as diethylamine, triethylamine, piperidine, piperazine,morpholine), or with basic amino-acids, or with osamines (such asmeglumine), or with aminoalcohols (such as 3-aminobutanol and2-aminoethanol).

The invention also relates to the salts used for chiral resolution ofthe racemates.

As examples, the following chiral acids can be used:(+)-D-di-O-benzoyltartaric acid, (−)-L-di-O-benzoyltartaric acid,(−)-L-di-O,O′-p-toluyl-L-tartaric acid,(+)-D-di-O,O′-p-toluyl-L-tartaric acid, (R)-(+)-O-malic acid,(S)-(−)-malic acid, (+)-camphoric acid, (−)-camphoric acid,R-(−)-1,1′-binaphtalen-2,2′-diyl hydrogenophosphonic, (+)-camphanicacid, (−)-camphanic acid, (S)-(+)-2-phenylpropionic acid,(R)-(+)-2-phenylpropionic acid, D-(−)-mandelic acid, L-(+)-mandelicacid, D-tartaric acid, L-tartaric acid, or any mixture of them.

As examples, the following chiral amines can be used: quinine, brucine,(S)-1-(benzyloxymethyl)propylamine (III), (−)-ephedrine,(4S,5R)-(+)-1,2,2,3,4-tetramethyl-5-phenyl-1,3-oxazolidine,(R)-1-phenyl-2-p-tolylethylamine, (S)-phenylglycinol,(−)-N-methylephedrine,(+)-(2S,3R)-4-dimethylamino-3-methyl-1,2-diphenyl-2-butanol,(S)-phenylglycinol, (S)-α-methylbenzylamine or any mixture of them.

Also included in the scope of the present invention are prodrugs of thecompounds of formula (I).

The term “prodrug” as used herein refers to any compound that whenadministered to a biological system generates the “drug” substance (abiologically active compound) as a result of spontaneous chemicalreaction(s), enzyme catalyzed chemical reaction(s), and/or metabolicchemical reaction(s).

in accordance with the present invention and as used herein, thefollowing terms are defined with the following meanings, unlessexplicitly stated otherwise.

The term “aryl” refers to aromatic groups which have 5-14 ring atoms andat least one ring having a conjugated pi (π) electron system andincludes biaryl groups, all of which may be optionally substituted.Suitable aryl groups include phenyl, naphthyl, biphenyl, anthryl,phenanthryl, indenyl and the like.

The term “heteroaryl” refers to 5-14 ring atom aromatic heterocyclescontaining 1 to 4 heteroatoms as ring atoms in the aromatic ring and theremainder of the ring atoms being carbon atoms. Suitable heteroatomsinclude O, S, N. Suitable heteroaryl groups include furanyl,benzofuranyl, thienyl, pyridyl, pyridyl-N-oxide, pyrimidinyl, pyrazinyl,oxazolyl, thiazolyl, isoxazolyl, quinolinyl, triazolyl, pyridazinyl,pyrrolyl, imidazolyl, indazolyl, isothiazolyl, indolyl, oxadiazolyl andthe like.

The term “cycloalkyl” means saturated carbocyclic rings, optionallysubstituted, and includes mono-, bi- and tri-cyclic compounds with 3 to10 carbon atoms. Suitable cycloalkyl groups are: cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,cyclodecyl, adamantyl and the like.

The term “heterocycloalkyl” refers to optionally substituted monocyclic,bicyclic or tricyclic radicals, comprising one or more heteroatoms,preferably chosen from among O, S and N, optionally in the oxidizedstate (for S and N), and optionally one or more double bonds. At leastone of the rings preferably comprises from 1 to 4 endocyclicheteroatoms, more preferably from 1 to 3 heteroatoms. Most preferably,the heterocycloalkyl (or simply “heterocyclic”) radical comprises one ormore rings, each having from 5 to 8 nodes. Examples of heterocyclicradicals are: morpholinyl, piperidinyl, piperazinyl, thiazolidinyl,oxazolidinyl, tetrahydrothienyl, dihydrofuranyl, tetrahydrofuranyl,pyrazolidinyl, 1,3-dioxolanyl, pyrrolidinyl, pyranyl, dihydropyranyl,isoxazolidinyl, imidazolyl, imidazolidinyl and the like.

The term “alkyl” refers to a saturated aliphatic groups, includingstraight chain and branched chain groups. Suitable alkyl groups, having1 to 20 carbon atoms, include methyl, ethyl, propyl, isopropyl, butyl,sec-butyl, tert-butyl, pentyl, hexyl, octyl, decanoyl, dodecanoyl,hexadecyl, octadecyl groups and the like.

The term “alkylene” refers to a divalent radial obtained from an alkylradical after one hydrogen atom has been withdrawn.

The term “alkenyl” refers to unsaturated groups comprising at least onecarbon-carbon double bond, and includes straight chain, branched chainand cyclic groups, Suitable alkenyl groups, having 2 to 20 carbon atoms,include ethenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl,3-pentenyl, 4-pentenyl and the like.

The term “alkynyl” refers to unsaturated groups comprising at least onecarbon-carbon triple bond and includes straight chain, branched chainand cyclic groups; and optionally includes at least one carbon-carbondouble bond. Suitable alkynyl groups, having 2 to 20 carbon atoms,include ethynyl, 2-propynyl, 2-butynyl, 3-butyryl, 2-pentynyl,3-pentynyl, 4-pentynyl and the like.

The term “arylalkyl” refers to an alkyl group, preferably an alkyl grouphaving 1 to 20 carbon atoms, substituted with an aryl group. Suitablearylalkyl groups include benzyl, picolyl, and the like.

The term “alkoxy” refers to the group alk-O— wherein “alk” is an alkylgroup.

The term “aryloxy” refers to the group aryl-O—.

The term “aryloxyalkyl” refers to an alkyl group substituted with anaryloxy group.

The term “arylalkoxy alkyl” refers to an alkyl group substituted with anarylalkoxy group.

The term “arylalkoxy” refers to the group aryl-Alk-O—, wherein “Alk” isan alkyl group.

The term “arylthioalkyl” refers to an alkyl group substituted with anarylthio group.

The term “arylalkylthioalkyl” refers to an alkyl group substituted withan arylalkylthio.

The term “heteroarylalkyl” refers to an alkyl group substituted with aheteroaryl group.

The term “heteroaryloxyalkyl” refers to an alkyl group substituted witha heteroaryloxy group.

The term “heteroarylalkoxyalkyl” refers to an alkyl group substitutedwith a heteroarylalkoxy group.

The term “heteroarylthioalkyl” refers to an alkyl group substituted witha heteroarylthio group.

The term “heteroarylalkylthioalkyl” refers to an alkyl group substitutedwith a heteroarylalkylthio group.

The term “heterocycloalkylalkyl” refers to an alkyl group substitutedwith a heterocycloalkyl group.

The term “heterocycloalkyloxyalkyl” refers to an alkyl group substitutedwith a heterocycloalkyloxy group.

The term “heterocycloalkylalkoxyalkyl” refers to an alkyl groupsubstituted with a heterocycloalkylalkoxy group.

The term “heterocycloalkylthioalkyl” refers to an alkyl groupsubstituted with a heterocycloalkylthio group.

The term “heterocycloalkylalkylthioalkyl” refers to an alkyl groupsubstituted with a heterocycloalkylalkylthio group.

The term “arylakenyl” refers to an alkenyl group substituted with anaryl group.

The term “arylalkynyl” refers to an alkynyl group substituted with anaryl group.

The term “alkyloxyalkyl” refers to an alkyl group substituted with analkyloxy group.

The term “cycloalkylalkyl” refers to an alkyl group substituted with acycloalkyl group.

The term “heterocycloalkyloxyalkyl” refers to an alkyl group substitutedwith a heterocycloalkyloxy group.

The term “heterocycloalkylalkoxyalkyl” refers to an alkyl groupsubstituted with a heterocycloalkylalkoxy group.

The term “heterocycloalkylthioalkyl” refers to an alkyl groupsubstituted with a heterocycloalkylthio group.

The term “heterocycloalkylalkylthioalkyl” refers to an alkyl groupsubstituted with a heterocycloalkylalkylthio group.

The term “lower” referred to herein in connection with organic radicalsor compounds respectively defines such as with up to and including 10,preferably up to and including 6, and advantageously one to four carbonatoms. Such groups may be straight, branched, or cyclic chain.

The term “aryle sulfonylalkyl” refers to the group aryle-SO₂-Alkwherein, “Alk” is an alkyl group.

The terms “alkylthio” refers to the group alkyl-S—, wherein “alk” is analkyl croup.

The term “halogen” refers to a fluorine, bromine or chlorine atom.

The term “amidino” refers to —C(NR3)-NR3R4 where R3R4 are as definedabove, all, except hydrogen, are optionally substituted.

The invention's compounds according to formula (I) exhibit anhypoglycemic activity, and are useful in the treatment of pathologiesassociated with the syndrome of insulin resistance,

Insulin resistance is characterised by a reduction in the action ofinsulin (cf. “Presse Medicale”, (1997), 26(14), 671-677) and is involvedin many pathological conditions, such as diabetes and more particularlynon-insulin-dependent diabetes (type II diabetes or NIDDM),dyslipidaemia, obesity, arterial hypertension, and also certain cardiac,microvascular and macrovascular complications, for instanceatherosclerosis, retinopathy and neuropathy. In this respect, referencewill be made, for Example, to Diabetes, 37, (1988), 1595-1607; Journalof Diabetes and its complications, 12, (1998), 110-119; Horm. Res., 38,(1992), 28-32.

The invention also relates to pharmaceutical composition containing asactive ingredient at least one compound of formula (I), as definedabove, and/or a pharmaceutically acceptable salt thereof, in combinationwith one or several pharmaceutically acceptable carrier, adjuvant,diluent or excipient. A person skilled in the art is aware of a wholevariety of such carrier, adjuvant, diluent or excipient compoundssuitable to formulate a pharmaceutical composition.

The pharmaceutical compositions of the present invention can beadministered by a variety of routes including oral, parenteral,intravenous, intramuscular, rectal, permucous or percutaneous.

They will thus be presented in the form of injectable solutions orsuspensions or multi dose bottles, in the form of plain or coatedtablets, sugar-coated tablets, wafer capsules, gel capsules, pills,sachets, powders, suppositories or rectal capsules, solutions orsuspensions, for percutaneous use in a polar solvent, or for permucoususe.

The excipients that are suitable for such administrations arepharmaceutically acceptable excipients, such as cellulose ormicrocrystalline cellulose derivatives, alkaline-earth metal carbonates,magnesium phosphate, starches, modified starches, lactose and the likefor solid forms.

For rectal use, cocoa butter or polyethylene glycol stearates are thepreferred excipients.

For parenteral use, water, aqueous solutions, physiological saline andisotonic solutions are the vehicles most appropriately used.

For example, in the case of an oral administration, for example in theform of granules, tablets or coated tablets, pills, capsules, gelcapsules, gels, cachets or powders, a suitable posology of the compoundsis between about 0.1 mg/kg and about 100 mg/kg, preferably between about0.5 mg/kg and about 50 mg/kg, more preferably between about 1 mg/kg andabout 10 mg/kg and most preferably between about 2 mg/kg and about 5mg/kg of body weight per day.

If representative body weights of 10 kg and 100 kg are considered, inorder to illustrate the daily oral dosage range that can be used and asdescribed above, suitable dosages of the compounds of the formula (I)will be between about 1-10 mg/per day and 1000-10000 mg/per day,preferably between about 5-50 mg/per day and 500-5000 mg/per day, morepreferably between 10-100 mg and 100-1000 mg/per day and most preferablybetween 20-200 mg and 50-500 mg/per day.

It will be understood, however, that the specific dose level for anyparticular patient will depend on a variety of factors including theactivity of the specific compound employed; the age, body weight,general health, sex and diet of the individual being treated; the timeand route of administration; the rate of excretion; other drugs whichhave previously been administered; and the severity of the particulardisease undergoing therapy, as is well understood by those skilled inthe art.

As noted above, formulations of the present invention suitable for oraladministration may be presented as discrete u its, such as capsules,cachets or tablets, each containing a predetermined amount of the activeingredient; as a powder or granules; as a solution or a suspension in anaqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion ora water-in-oil liquid emulsion. The active ingredient may also beadministered as a bolus, electuary or paste.

The present invention also relates to compound of general formula (I) aswell as its racemic forms, tautomers, enantiomers, diastereomers,epimers and polymorphs, and mixtures thereof, and the pharmaceuticallyacceptable salts thereof, for the preparation of a medicament for theprevention and/or treatment of pathologies associated withhyperglycaemia; for the preparation of a medicament that induces insulinsecretion in response of glucose concentration, preferably for thetreatment of diabetes, more preferably for the prevention and/ortreatment of type II diabetes and pathologies associated to metabolicdisorders, hypercholesteremia, hyperlipidemia, which are increased byhyperinsulinemia and hyperglycemia; for the treatment of diseases chosenfrom diabetes related microvascular and macrovascular complications,such as arterial hypertension, inflammatory processes, microangiopathy,macroangiopathy, retinopathy and neuropathy; for reducinghyperglycaemia, for the treatment of dyslipidaemia and obesity; ordiseases such as cardiovascular diseases, comprising atherosclerosis,myocardial ischemia.

The present invention also relates to the use of at least a compound ofthe general formula (I), as well as its racemic forms, tautomers,enantiomers, diastereomers, epimers and polymorphs, and mixturesthereof, and the pharmaceutically acceptable salts, and pro-drugsthereof, for the prevention and/or treatment of pathologies associatedwith hyperglycaemia, preferably for the treatment of diabetes, morepreferably for the prevention and/or treatment of type II diabetes andpathologies associated to metabolic disorders, hypercholesteremia,hyperlipidemia, which are increased by hyperinsulinemia andhyperglycemia; for the treatment of diseases chosen from diabetesrelated microvascular and macrovascular complications, such as arterialhypertension, inflammatory processes, microangiopathy, macroangiopathy,retinopathy and neuropathy; for reducing hyperglycaemia, for thetreatment of dyslipidaemia and obesity; or diseases such ascardiovascular diseases, comprising atherosclerosis, myocardialischemic.

The present invention also relates to manufacturing process of compoundsof formula (I), as defined above, according to the followingrepresentative methods shown in Scheme 1 (Preparation of theIntermediates diaminopyridine derivatives); Scheme 2 (Method A) orScheme 3 (Method B), in which X, Y, Z, W, R1, A are as defined above informula (I) and Hal is a halogen atom, preferably Cl or Sr.

The following schemes are given for representative purposes, and solelyfor the purpose of facilitating the representation, Needless to say,depending on the nature of the compounds of the formula (I) to beobtained, the methodologies presented may be adapted by a person skilledin the art by selecting the appropriate starting materials, in which thenature of the substituents R1 and A may be modified, especially as afunction of the nature and length of the desired chain.

The compounds useful according to the invention may be prepared, unlessspecifically specified, by the application or adaptation of knownmethods, by which are meant methods used heretofore or described in theliterature, patents or patent applications, the Chemical Abstracts andon the Internet.

Preparation of the Intermediates Diaminopyridine Derivatives:

wherein:Hal is a halogen atom, preferably Cl, Br;R1 is as above defined in formula (I);X, Y, Z and W are as above defined in formula (I).

Pyridine nitro amino derivatives of formula (2) are prepared by reactingan halo-nitropyridine derivative of formula (1) with an amine, in thepresence of at least one equivalent of a base, such as sodium orpotassium carbonate, cesium carbonate, or in the presence of at leasttwo equivalents of the considered amine, in an inert solvent, such astetrahydrofurane, acetonitrile or toluene, at a temperature between 20°C. and the reflux for 1 to 24 h. Diamino pyridine derivatives of formula(3) may be prepared from compounds of formula (2) by reduction of thenitro to the corresponding primary aromatic amine. Preferred methods usemetal, such as Zn, Sn or Fe, in acids, such as aqueous HCl. Otherpreferred method, use metal in lower state of oxidation, such asSn(II)chloride in HCl. Particularly preferred is the reduction bycatalytic hydrogenation, which uses metal catalysts from metals such asPd, Pt or Ni, preferably Pd on charcoal or Raney Nickel in solvents suchas methanol, ethanol, tetrahydrofurane.

Preparation of the Pyridopyrazinone Derivatives:

This method is particularly suitable for compounds of formula (I),wherein:

Rx is Hal, ORe (wherein Re is hydrogen, lower alkyl);Hal is a halogen atom, preferably Cl, Br;R1 is as above defined in formula (I);A is as above defined in formula (I);X, Y, Z and W are as above defined in formula (I).

Pyridopyrazinones of formula (I) are prepared by cyclization ofcompounds of formula (3) with an α-keto acid derivative in a solvent,such as, for example, methanol, acetonitrile, dimethylformamide (DMF) ortoluene, at a temperature between 20° C. and the reflux, more preferablyreflux, for 1 to 36 h.

This method is particularly suitable for compounds of formula (I),wherein:

Rx is Hal, ORe (wherein Re is hydrogen, lower alkyl);Hal is a halogen atom, preferably Cl, Br;R1 is as above defined in formula (I):A is as above defined in formula (I);X, Y, Z and W are as above defined in formula (I).

Hydroxypyridopyrazinones of formula (5) are obtained by cyclization ofcompounds of formula (3) with, for example, chloro(oxo)acetatederivatives in the presence of at least one equivalent of a base, aninorganic base, such as sodium or potassium carbonate, cesium carbonate,or an organic base, such as triethylamine or diisopropylethylamine, in ainert solvent, such as, for example, dichloromethane, acetonitrile, DMF,at a temperature between 20° C. and the reflux, for 1 to 24 h.

Bromo derivatives of formula (6) are prepared by bromination ofcompounds of formula (5) using a brominating agent, such as POBr₃, in aninert solvent, such as 1,2-dichloroethane, at a temperature between 20°C. and the reflux, more preferably reflux for to 24 h.

Pyridopyrazinones of formula (I) are prepared by reacting the bromocompounds of formula (6) with boronic acid derivatives or their esters,in the presence of a base, such as sodium carbonate or potassiumcarbonate, and a catalyst, such as bis(triphenylphosphine)palladium(II)chloride, in an inert solvent, such as dimethylformamide ortoluene, at a temperature between 20° C. and the reflux, more preferablyreflux, for 1 to 24 h.

The examples that follow illustrate the invention without, however,limiting it.

The starting materials used are known products or products preparedaccording to known procedures. The percentages are expressed on a weightbasis, unless otherwise mentioned.

The compounds were characterised especially via the following analyticaltechniques.

The NMR spectra were acquired using a Bruker Avance DPX 300 MHz NMRspectrometer.

The masses were determined by HPLC coupled to an Agilent Series 1100mass detector. The melting points (m.p.) were measured on a StuartScientific block.

EXAMPLES Example 1 N-(cyclopropylmethyl)-3-nitropyridin-2-amine

3 g (18.9 mM) of 2-chloro-3-nitropyridine and 5 g (70.3 mM) ofcyclopropylmethylamine in 12 ml of tetrahydrofurane were refluxed understirring for 1 h. Water was added and the aqueous layer was extractedwith ethylacetate. The organic layer was washed with water and driedover anhydrous sodium sulfate. The solvent was removed under vacuum togive 3.5 g of N-(cyclopropylmethyl)-3-nitropyridin-2-amine as a yellowoil. Yield: 95.7%.

NMR ¹H (300 MHz/DMSO-d6) δ (ppm): 0.06 (m, 2H), 0.24 (m, 2H), 0.95 (m,1H) 3.22 (t, 1H), 6.53 (m, 1H) 8.18 (m, 1H), 8.25 (m, 1H), 8.31 (m, 1H)

The following compounds were obtained using the same procedure as inExample 1.

Example 1-2 N-(2,2-difluoroethyl)-3-nitropyridin-2-amine

C₇H₁F₂N₃O₂=203.15 Mass spectrometry M+1=204

Example 1-3 N-cyclopropyl-3-nitropyridin-2-amine

C₈H₉N₃O₂=179.18 Mass spectrometry M+1=180.0

Example 1-4 N-(cyclopropyl)-3-nitropyridin-4-amine

NMR ¹H (300 MHz/DMSO-d6δ (ppm): 0.46 (m, 2H), 0.67 (m, 2H), 2.45 (m,1H), 7.05 (d, 1H), 8.05 (s, 1H), 8.14 (d, 1H), 8.79 (s, 1H)

Example 1-5 N-(cyclopropylmethyl)-3-nitropyridin-4-amine

NMR ¹H (300 MHz/DMSO-d6) δ (ppm): 0.20 (m, 2H), 0.39 (m, 2H), 1.05 (m,1H), 3.17 (t, 2H), 6.94 (d, 1H), 8.15 (d, 1H), 8.33 (s, 1H), 8.91 (s,1H)

Example 2 N²-(cyclopropylmethyl)pyridine-2,3-diamine

To a solution of 3.5 g (18.1 mM) ofN-(cyclopropylmethyl)-3-nitropyridin-2® amine in 36 ml of methanol, wereadded 700 mg of palladium on carbon at 5%. The reaction mixture wasstirred for 3 h at room temperature under hydrogen atmosphere at roompressure. The catalyst was filtrated on Celite and the filtrate wasevaporated under vacuum to give 3.1 g ofN²-(cyclopropylmethyl)pyridine-2,3-diamine as a solid. Yield: 99.5%.

NMR ¹H (300 MHz/DMSO-d6) δ (ppm): 0.00 (m, 2H), 0.24 (m, 2H), 0.89 ((m,1H), 2.96 (t, 2H), 4.5 (s, 2H), 5.37 (t, 1H), 6.15 (m, 1H), 6.44 (d,1H), 7.13 (1d, 1H)

The following compounds were obtained using the same procedure as inExample 2

Example 2-2 N²-(2,2-difluoroethyl)pyridine-2,3-diamine

C₇H₉F₂N₃=173.16 Mass spectrometry M+1=174.1

Example 2-3 N²-cyclopropylpyridine-2,3-diamine

C₈H₁₁N₃=149.19 Mass spectrometry M+1=150.1

Example 2-4 N⁴-cyclopropylpyridine-3,4-diamine

NMR ¹H (300 MHz/DMSO-d6) δ (ppm): 0.29 (m, 2H), 0.61 (m, 2H), 2.23 (m,1H), 4.40 (s, 2H), 5.65 (s, 1H), 6.50 (d, 1H), 7.49 (m, 2H)

Example 2-5 N⁴-(cyclopropylmethyl)pyridine-3,4-diamine

NMR ¹H (300 MHz/DMSO-d6) δ (ppm): 0.02 (m, 2H), 0.28 (m, 2H), 0.84 (m,1H), 2.74 (t, 2H), 4.41 (s, 2H), 5.19 (m, 1H), 6.14 (d, 1H), 7.35 (d,1H), 7.41 (s, 1H)

Method A Example 32-(4-chlorophenyl)-4-cyclopropylmethylpyrido[2,3-b]pyrazin-3(4H)-one

430 mg (2.63 mM) of N²-(cyclopropylmethyl)pyridine-2,3-diamine and 485.4mg (2.63 mM) of (4-chlorophenyl)(oxo)acetic acid in 6 ml of methanolwere refluxed for 16 h. A solid crystallized. The compound was filteredand washed with methanol to give

300 mg of2-(4-chlorophenyl)-4-(cyclopropylmethyl)pyrido[2,3-b]pyrazin-3(4H)-oneas a beige solid. Yield: 36.5%.

NMR ¹H (300 MHz/CF₃COOD) δ (ppm): 0.59 (m, 4H), 1.23 (m, 1H), 4.44 (d,2H), 7.44 (d, 2H), 7.83 (m, 1H), 8.11 (d, 2H), 8.66 (d, 1H), 8.89 (d,1H)

The following compounds were obtained using the same procedure as inExample 3.

Example 3-2 2,2-(4-chlorophenyl)-4-ethylpyrido[2,3-b]pyrazin-3(4H)-one

NMR ¹H (300 MHz/CF₃COOD) δ (ppm): 0.18 (t, 3H), 3.30 (q, 2H), 6.16 (d,2H), 6.55 (m, 1H), 6.84 (d, 2H), 7.37 (d, 1H), 7.63 (d, 1H)

Example 3-3 2-(4-fluorophenyl)-4-ethylpyrido[2,3-b]pyrazin-3(4H)-one

NMR ¹H (300 MHz/DMSO-d6) δ (ppm): 1.30 (t, 3H), 4.47 (q, 2H), 7.36 (t,2H), 7.51 (m, 1H), 8.33 (m, 3H), 8.69 (d, 1H)

Example 3-4 4-ethyl-2-phenylpyrido[2,3-b]pyrazin-3(4H)-one

NMR ¹H (300 MHz/DMSO-d6) δ (ppm): 1.30 (t, 3H), 4.47 (1.2H), 7.54 (m,4H), 8.24 (m, 3H), 8.67 (d, 1H)

Example 3-52-(4-chlorophenyl)-4-cyclopropylpyrido[2,3-b]pyrazin-3(4H)-one

NMR ¹H (300 MHz/CF₃COOD) δ (ppm): 1.15 (m, 2H), 1.60 (m, 2H), 3.27 (m,1H), 7.40 (d, 2H), 7.83 (m, 1H), 8.13 (d, 2H), 8.64 (d, 1H), 8.86 (d,1H)

C₁₆H₁₂ClN₃O=297.74 Mass spectrometry M+1=298.0

Example 3-64-cyclopropyl-2-(4-fluorophenyl)pyrido[2,3-b]pyrazin-3(4H)-one

NMR ¹H (300 MHz/CF₃COOD) δ (ppm): 1.10 (m, 2H), 1.57 (m, 2H), 3.23 (m,1H), 7.06 (m, 2H), 7.79 (m, 1H), 8.15 (m, 2H), 8.59 (d, 1H), 8.83 (d,1H)

C₁₆H₁₂FN₃O=281.23 Mass spectrometry M+1=282.1

Example 3-74-cyclopropylmethyl-2-(4-fluorophenyl)pyrido[2,3-b]pyrazin-3(4H)-one

NMR ¹H (300 MHz/DMSO-d6) δ (ppm): 0.46 (m, 4H), 1.33 (m, 1H), 4.34 (d,2H), 7.34 (1.2H), 7.49 (m, 1H), 8.30 (m, 3H), 8.65 (d, 1H)

Example 3-82-(4-chlorophenyl)-4-(2,2-difluoroethyl)pyrido[2,3-b]pyrazin-3(4H)-one

NMR ¹H (300 MHz/DMSO-d6) δ (ppm): 4.88 (td, 2H), 6.41 (tt, 1H), 7.59 (m,3H), 8.28 (m, 3H), 8.66 (d, 1H)

Example 3-93-(4-chlorophenyl)-1-cyclopropylpyrido[3,4-b]pyrazin-2(1H)-one

NMR ¹H (300 MHz/DMSO-d6) δ ppm): 0.97 (m, 2H), 1.36 (m, 2H), 3.12 (m,1H), 7.63 (d, 2H), 7.82 (d, 1H), 8.29 (d, 2H), 8.66 (d, 1H), 9.04 (s,1H)

C₁₆H₁₂ClN₃O=297.74 Mass spectrometry M+1=298.0

Example 3-101-cyclopropyl-3-(4-fluorophenyl)pyrido[3,4-b]pyrazin-2(1H)-one

C₁₆H₁₂FN₃O=281.28 Mass spectrometry M+1=282.0

Example 3-11 1-cyclopropyl-3-phenylpyrido[3,4-b]pyrazin-2(1H)-one

C₁₆H₁₃N₃O=263.29 Mass spectrometry M+1=264.1

Example 3-121-cyclopropyl-3-[4-(trifluoromethyl)phenyl]pyrido[3,4-b]pyrazin-2(1H)-one

C₁₇H₁₂F₃N₃O=331.29 Mass spectrometry M+1=332.0

Example 3-132-(4-chlorophenyl)-4-cyclopropyl-8-methylpyrido[2,3-b]pyrazin-3(4H)-one

NMR ¹H (300 MHz/DMSO-d6) δ (ppm): 0.92 (m, 2H) 1.25 (m, 2H) 2.89 (s, 3H)3.08 (m, 1H) 7.36 (d, 1H) 7.61 (d, 2H) 8.34 (d, 2H) 8.52 (d, 1H)

C₁₇H₁₄ClN₃O=311.77 Mass spectrometry M+1=312.0

m.p.: 159-163° C.

Example 3-144-cyclopropyl-2-(4-fluorophenyl)-6-methylpyrido[2,3-b]pyrazin-3(4H)-one

C₁₇H₁₄FN₃O=295.31 Mass spectrometry M+1=296.0

Example 3-152-(4-chlorobenzyl)-4-cyclopropylpyrido[2,3-b]pyrazin-3(4H)-one

NMR ¹H (300 MHz/CDCl₃) δ (ppm): 0.86 (q, 2H), 1.28 (q, 2H), 3.00 (1H),4.12 (s, 2H), 7.19 (m, 3H), 7.30 (d, 2H), 8.02 (d, 1H), 8.50 (m, 1H)

Example 3-162-(4-fluorophenyl)-4-(2-methoxyethyl)pyrido[2,3-b-]pyrazin-3(4H)-one

C₁₆H₁₄FN₃O₂=299.3 Mass spectrometry M+1=300.0

m.p.: 124-127° C.

Example 3-17 4-butyl-2-(4-chlorophenyl)-pyrido[2,3-b]pyrazin-3(4H)-one

C₁₇H₁₆ClN₃O=313.79 Mass spectrometry M+1=314.0

Example 3-182-(4-chlorophenyl)-4-isopropyl-pyrido[2,3-b]pyrazin-3(4H)-one

NMR ¹H (300 MHz/DMSO-d6) δ (ppm): 1.55 (d, 6H), 5.36 (m, 1H), 7.40 (m,1H), 7.50 (d, 2H), 8.15 (d, 2H), 8.20 (d, 1H), 8.60 (d, 1H)

C₁₆H₁₄ClN₃O=299.76 Mass spectrometry M+1=299.7

Example 3-194-cyclopropyl-2-(4-trifluoromethylphenyl)-pyrido[2,3-b]pyrazin-3(4H)-one

C₁₇H₁₂F₃N₃O=331.29 Mass spectrometry M+1=332.1

Example 3-204-cyclopropylmethyl-2-(4-trifluoromethylphenyl)pyrido[2,3-b]pyrazin-3(4H)-one

C₁₈H₁₄F₃N₃O=345.32 Mass spectrometry M+1=346.1

Example 3-214-(2,2-difluoroethyl)-2-phenylpyrido[2,3-b]pyrazin-3(4H)-one

C₁₅H₁₁F₂N₃O=287.27 Mass spectrometry M+1=288.0

Example 3-224-(2,2-difluoroethyl)-2-(4-fluorophenyl)pyrido[2,3-b]pyrazin-3(4H)-one

C₁₅H₁₀F₃N₃O=305.27 Mass spectrometry M+1=306.0

Example 3-234-(2,2-difluoroethyl)-2-(4-trifluoromethylphenyl)pyrido[2,3-b]pyrazin-3(4H)-one

C₉H₁₀F₅N₃O=355.27 Mass spectrometry M+1=356.0

Example 3-244-(2-methoxyethyl)-2-(4-trifluoromethylphenyl)-pyrido[2,3-b]pyrazin-3(4H)-one

C₁₇H₁₄F₃N₃O₂=349.31 Mass spectrometry M+1=350.1

Example 3-252-(4-chlorophenyl)-4-(2-methoxyethyl)pyrido[2,3-b]pyrazin-3(4H)-one

C₁₆H₁₄ClN₃O₂=315.76 Mass spectrometry M+1=316.0

Example 3-26 4-(2-methoxyethyl)-2-phenylpyrido[2,3-b]pyrazin-3(4H)-one

C₁₆H₁₅N₃O₂=281.31 Mass spectrometry M+1=282.1

Example 3-274-cyclopropyl-2-(4-trifluoromethylphenyl-8-methylpylido[2,3-b]pyrazin-3(4H)-one

C₁₈H₁₄F₃N₃O=345.32 Mass spectrometry M+1=346.3

Example 3-284-cyclopropyl-2-(4-fluorophenyl)-8-methylpyrido[2,3-b]pyrazin-3-(4H)-one

C₁₇H₁₄FN₃O=295.32 Mass spectrometry M+1=296.1

Example 3-29 4-cyclopropylmethyl-2-phenylpyrido[2,3-b]pyrazin-3(4H)-one

C₁₇H₁₅N₃O=277.33 Mass spectrometry M+1=278.1

Example 3-302-(4-chlorophenyl)-4-cyclopropyl-7-methylpyrido[2,3-b]pyrazin-3(4H)-one

C₁₇H₁₄ClN₃O=311.77 Mass spectrometry M+1=312.0

Example 3-314-cyclopropyl-2-(4-fluorophenyl)-7-methylpyrido[2,3-b]pyrazin-3(4H)-one

C₁₇H₁₄FN₃O=295.32 Mass spectrometry M+1=296.1

Example 3-322-(4-fluoro-phenyl)-4-isopropyl-pyrido[2,3-b]pyrazin-3(4H)-one

C₁₇H₁₄FN₃O=283.30 Mass spectrometry M+1=284.1

Example 3-33 4-isopropyl-2-phenylpyrido[2,3-b]pyrazin-3(4H)-one

C₁₆H₁₅N₃O=265.31 Mass spectrometry M+1=266.1

Example 3-342-(4-chlorophenyl)-4-cyclopropyl-6-methylpyrido[2,3-b]pyrazin-3(4H)-one

C₇H₁₄ClN₃O=311.77 Mass spectrometry M+1=312.0

Example 3-35 4-cyclopropyl-2-phenylpyrido[2,3-b]pyrazin-3(4H)-one

C₁₆H1₃N₃O=263.29 Mass spectrometry M+1=264.1

Example 3-364-cyclopropyl-2-(4-fluorophenyl)-6-methoxypyrido[2,3-b]pyrazin-3(4H)-one

C₁₇H₁₄FN₃O₂=311.31 Mass spectrometry M+1=312.1

Example 3-374-cyclobutyl-2-(4-fluorophenyl)pyrido[2,3-b]pyrazin-3(4H)-one

C₁₇H₁₄FN₃O=295.31 Mass spectrometry M+1=296.1

Example 3-382-(4-Chlorophenyl)-4-(2-hydroxyethyl)pyrido[2,3-b]pyrazin-3(4H)-one

C₁₅H₁₂ClN₃O₂=301.73 Mass spectrometry M+1=302.0

Example 3-392-(4-Fluorophenyl)-4-(2-hydroxyethyl)pyrido[2,3-b]pyrazin-3(4H)-one

C₁₅H₁₂FN₃O₂=285.28 Mass spectrometry M+1=286.1

Example 3-40 4-(2-hydroxyethyl)-2-phenylpyrido[2,3-b]pyrazin-3(4H)-one

C₁₅H₁₃N₃O₂=267.29 Mass spectrometry M+1=268.1

Example 3-412-(4-Chlorophenyl)-4-(3-hydroxypropyl)pyrido[2,3-b]pyrazin-3(4H)-one

C₁₆H₁₄ClN₃O₂=315.76 Mass spectrometry M+1=316.1

Example 3-422-(4-Fluorophenyl)-4-(3-hydroxypropyl)pyrido[2,3-b]pyrazin-3(4H)-one

Cl₆H₁₄FN₃O₂=299.30 Mass spectrometry M+1=300.1

Example 3-43 4-(3-Hydroxypropyl)-2-phenylpyrido[2,3-b]pyrazin-3(4H)-one

C₁₆H₁₅N₃O₂=281.31 Mass spectrometry M+1=282.1

Example 3-44 1-ethyl-3-(4-fluorophenyl)pyrido[2,3-b]pyrazin-2(1H)-one

C₁₅H₁₂FN₃O=269.27 Mass spectrometry M+1=270.0

Example 3-452-(4-fluorophenyl)-4-[2-(diethylamino)ethyl]pyrido[2,3-b]pyrazin-3(4H)-one

C₁₉H₂₁FN₄O=340.39 Mass spectrometry M+1=341.1

Example 3-462-(4-chlorophenyl)-4-[2-(diethylamino)ethyl]pyrido[2,3-b]pyrazin-3(4H)-one

C₁₉H₂₁ClN₄O=356.85 Mass spectrometry M+1=357.1

Method B Example 44-(cyclopropylmethyl)-2-hydroxypyrido[2,3-b]pyrazin-3(4H)-one

To 1.6 g (9.8 mM) of N²-(cyclopropylmethyl)pyridine-2,3-diamine and 1.7ml (9.8 mM) of diisopropylamine in 20 ml of dichloromethane were added,drop by drop, under stirring; at room temperature, 1.1 ml (9.8 mM) ofethyl chloro(oxo)acetate. The reaction mixture was stirred at roomtemperature for 16 h and water was added. The organic layer wasseparated and the aqueous layer was extracted twice withdichloromethane. The combined organic layer was washed with water, driedon anhydrous sodium sulfate and the solvent was removed under vacuum.The compound was further purified by silica gel column chromatographyusing dichloromethane/methanol (95/5) as eluant, which afforded afterevaporation 700 mg of4-(cyclopropylmethyl)-2-hydroxypyrido[2,3-b]pyrazin-3(4H)-one as asolid. Yield: 33%.

NMR ¹H (300 MHz/DMSO-d6) δ (ppm): 0.19 (m, 4H), 1.03 (m, 1H), 3.90 (d,2H), 6.98 (m, 1H), 7.29 (d, 1H), 7.96 (d, 1H), 11.94 (s, 1H)

The following compounds were obtained using the same procedure as inExample 4.

Example 4-2 4-(cyclopropyl)-2-hydroxypyrido[2,3-b]pyrazin-3(4H)-one

C₁₀H₉N₃O₂=203.2 Mass spectrometry M+1=204.0

Example 5 2-bromo-4-(cyclopropylmethyl)pyrido[2,3-b]pyrazin-3(4H)-one

700 mg (3.22 mM) of4-(cyclopropylmethyl)-2-hydroxypyrido[2,3-b]pyrazin-3(4H)-one and 972.3mg (3.22 mM) of phosphorus oxybromide at 95% in 10 ml of dichloroethanewere refluxed for 16H under stirring. The reaction mixture was thenbasified with an aqueous solution of sodium carbonate and the aqueouslayer was extracted with dichloromethane. The organic layer wasseparated, washed with water, dried on anhydrous sodium sulfate and thesolvent was removed under vacuum. The compound was further purified bysilica gel column chromatography, using dichloromethane as eluant, togive, after evaporation, 650 mg of2-bromo-4-(cyclopropylmethyl)pyrido[2,3-b]pyrazin-3(4H)-one as a whitesolid. Yield: 66.5%.

NMR ¹H (300 MHz/DMSO-d6) δ (ppm): 0.46 (m, 4H), 1.31 (m, 1H), 4.26 (d,2H), 7.49 (m, 1H), 8.22 (d, 1H), 8.68 (d, 1H)

The following compounds were obtained using the same procedure as inExample 5.

Example 5-2 2-bromo-4-(cyclopropyl)pyrido[2,3-b]pyrazin-3(4H)-one

C₁₀H₈BrN₃O=266.1 Mass spectrometry M+1=267.0

m.p.: 144-146° C.

Example 64-(cyclopropylmethyl)-2-(4-fluoro-2-ethylphenyl)pyrido[2,3-b]pyrazin-3(4H)-one

To 200 mg (0.71 mM) of2-bromo-4-(cyclopropylmethyl)pyrido[2,3-b]pyrazin-3(4H)-one and 25.3 mg(0.036 mM) of bis(triphenylphosphine) palladium(II)chloride in 1 ml ofdimethylformamide were added 142.9 mg (0.93 mM) of(4-fluoro-2-methylphenyl)boronic acid, 0.1 ml of ethanol and 715 μl of a2M aqueous solution of sodium carbonate. The reaction mixture was thenrefluxed for 20 h under stirring. Water and ethyl acetate were added.The organic layer was separated, washed with water, dried on anhydroussodium sulfate and the solvent was removed under vacuum. The compoundwas further purified by silica gel column chromatography, usingdichloromethane as eluant, to give, after evaporation, 100 mg of4-(cyclopropylmethyl)-2-(4-fluoro-2-methylphenyl)pyrido[2,3-b]pyrazin-3(4H)-one as awhite solid. (Yield: 45.3%)

NMR ¹H (300 MHz/DMSO-d6) δ (ppm): 0.27 (m, 4H), 1.15 (m, 1H), 4.10 (d,2H), 6.96 (m, 2H), 7.31 (m, 2H), 8.08 (d, 1H), 8.48 (d, 1H)

C₁₈H₁₆FN₃O 309.34 Mass spectrometry M+1=310.1

The following compounds were obtained using the same procedure as inExample 6.

Example 6-24-cyclopropyl-2-(4-fluoro-2-methylphenyl)pyrido[2,3-b]pyrazin-3(4H)-one

C₁₇H₁₄FN₃O=295.31 Mass spectrometry M+1=296.1

m.p.: 165-167° C.

Example 6-32-(4-chloro-2-methylphenyl)-4-cyclopropylpyrido[2,3-b]pyrazin-3(4H)-one

C₁₇H₁₄ClN₃O=311.76 Mass spectrometry M+1=312.0

Example 6-44-cyclopropyl-2-(3-fluorophenyl)-pyrido[2,3-b]pyrazin-3(4H)-one

C₁₆H₁₂FN₃O=281.29 Mass spectrometry M+1=282.1

Example 6-52-(3-chlorophenyl)-4-cyclopropylpyrido[2,3-b]pyrazin-3(4H)-one

C₁₆H₁₂ClN₃O=297.74 Mass spectrometry 298.0

Example 6-64-cyclopropyl-2-(3-methylphenyl)pyrido[2,3-b]pyrazin-3(4H)-one

C₁₇H₁₅N₃O=277.32 Mass spectrometry M+1=278.1

Example 6-74-cyclopropylmethyl-2-(4-fluoro-2-methylphenyl)-pyrido[2,3-b]pyrazin-3(4H)-one

C₁₈H₁₆FN₃O=309.34 Mass spectrometry M+1=310.1

Example 6-8 4-cyclopropyl-2-(4-methylphenyl)pyrido[2,3-b]pyrazin3(4H)-one

C₁₇H₁₅N₃O=277.32 Mass spectrometry M+1=278.1

Example 6-94-cyclopropyl-2-[3-(trifluoroethyl)phenyl]pyrido[2,3-b]pyrazin-3(4H)-one

C₁₇H₁₂F₃N₃O=331.29 Mass spectrometry M+1=332.1

Example 6-102-(2-Chlorophenyl)-4-cyclopropylpyrido[2,3-b]pyrazin-3(4H)-one

C₁₆H₁₂ClN₃O=297.74 Mass spectrometry M+1=298.0

Example 6-114-Cyclopropyl-2-(2,4-dichlorophenyl)pyrido[2,3-b]pyrazin-3(4H)-one

C₁₆H₁₁Cl₂N₃O=332.18 Mass spectrometry M+1=333.2

Example 6-124-Cyclopropyl-2-(2,4,5-trifluorophenyl)pyrido[2,3-b]pyrazin-3(4H)-one

C₁₆H₁₀F₃N₃O=317.27 Mass spectrometry M+1=318.0

Example 6-134-Cyclopropyl-2-(2-methoxyphenyl)pyrido[2,3]pyrazin-3(4H)-one

C₁₇H₁₅N₃O₂=293.32 Mass spectrometry M+1=294.1

Example 6-144-Cyclopropyl-2-(4-methoxyphenyl)pyrido[2,3-b]pyrazin-3(4H)-one

C₁₇H₁₅N₃O₂=293.32 Mass spectrometry M+1=294.1

Example 6-152-(4-Chloro-2-methylphenyl)-4-isopropylpyrido[2,3-]pyrazin-3(4H)-one

C₁₇H₁₆ClN₃O=313.78 Mass spectrometry M+1=314.0

Example 6-162-(2,4-Dichlorophenyl)-4-isopropylpyrido[2,3-b]pyrazin-3(4H)-one

C₁₆H₁₃Cl₂N₃O=334.20 Mass spectrometry M+1=334.0

Example 6-172-(4-Fluoro-2-methylphenyl)-4-isopropylpyrido[2,3-b]pyrazin-3(4H)-one

C₁₇H₁₆FN₃O=297.33 Mass spectrometry M+1=298.1

Example 6-182-(2-Ethoxyphenyl)-4-isopropylpyrido[2,3-b]pyrazin-3(4H)-one

C₁₈H₁₉N₃O₂=309.36 Mass spectrometry M+1=310.1

Example 6-194-cyclopropyl-2-(6-methoxypyridin-3-yl)pyrido[2,3-b]pyrazin-3(4H)-one

C₁₆H₁₄N₄O₂=294.31 Mass spectrometry M+1=295.1

Example 6-20 4-cyclopropyl-2-(2-thienyl)pyrido[2,3-b]pyrazin-3(4-one

C₁₄H₁₁N₃OS=269.32 Mass spectrometry M+1=270.0

Example 6-21 4-cyclopropyl-2-(2-furyl)pyrido[2,3-b]pyrazin-3(4H)-one

C₁₄H₁₁N₃O₂=253.26 Mass spectrometry M+1=254.0

Example 6-222-(4-chloro-2-ethylphenyl)-4-(2-hydroxyethyl)pyrido[2,3-b]pyrazin-3(4H)-one

C₁₆H₁₄ClN₃O₂=315.75 Mass spectrometry M+1=316.0

Example 6-232-(4-fluoro-2-methylphenyl)-4-(2-hydroxyethyl)pyrido[2,3-b]pyrazin-3(4H)-one

C₁₆H₁₄FN₃O₂=299.3 Mass spectrometry M+1=300.1

Example 6-242-(4-chloro-2-methylphenyl)-4-(2-methoxyethyl)pyrido[2,3-b]pyrazin-3(4H)-one

C₁₇H₁₆ClN₃O₂=329.78 Mass spectrometry M+1=330.0

Example 6-252-(4-fluoro-2-methylphenyl)-4-(2-methoxyethyl)pyrido[2,3-b]pyrazin-3(4H)-one

C₁₇H₁₆FN₃O₂=313.33 Mass spectrometry M+1=314.1

Example 6-264-cyclopropyl-2-(2,4-dimethylphenyl)pyrido[2,3-b]pyrazin-3(4H)-one

C₁₈H₁₇N₃O=291.35 Mass spectrometry M+1=292.1

Biological Assays

The INS-1 cells were selected to evaluate compounds of the presentinvention for their superior response to glucose and other physiologicaland pharmacological insulin secretagogues.

Culture of Pancreatic INS-1 Cells

INS-1 cells were cultured in complete medium, RPMI1640 containing 1 mMsodium pyruvate, 50 μM 2-mercaptoethanol, 2 mM glutamine, 10 mM HEPES,100 IU/mL penicillin, and 100 μg/mL streptomycin (CM), supplemented with10 mM glucose, and 10% (vol/vol) heat-inactivated fetal calf serum(FCS), as described by Asfari et al. (Endocrinology 130: 167-178, 1992).

Insulin Secretion Assay

INS-1 cells were plated and cultured in 48-well plates. After 2 days ofculture, the medium was removed and cells were cultured for 24 h with amedium change to 5 mM glucose, 1% FCS. The cells were then washed withKrebs-Ringer Bicarbonate HEPES buffer (KRBH; 135 mM NaCl; 3.6 mM KCl; 5mM NaHCO3; 0.5 mM NaH2PO4; 0.5 mM MgCl2; 1.5 mM CaCl2 and 10 mM HEPES;pH 7.4) 0.1% BSA containing 2.8 mM glucose and preincubated for 30 minat 37° C. in the same buffer. The cells were then washed twice andincubated for 1 h in KRBH 0.1% BSA containing 4.2 mM glucose anddifferent concentrations of the tested molecule. Insulin concentrationin the collected supernatants was measured with ELISA using rat insulinantibody (Insulin Rat Elit PLUS, cat, ref 10-1145-01).

Insulin secretion results are expressed in % of control (glucose 4.2mM).

Insulin Secretion in INS-1 Cells (Glucose at 4.2 mM)

% of ctrl at % of ctrl at Example 10 μM of cpd 50 μM of cpd 3 241 3983-2 240 283 3-3 235 251 3-4 226 302 3-5 418 610 3-6 231 255 3-7 208 2213-8 273  3-16 254  3-18 338

Insulin Secretion in Diabetic NOSTZ Rat Islets. Materials and Methods.Islets Isolation and Treatments.

14±3 weeks non-fasted NOSTZ (PORTHA et al., 1974) male rats (CharlesRivers-Domaine des Oncins, I'Arbresle, France) were anesthetised withsodium pentobarbital (Nembutal® 45 mg/kg in 5 ml/kg administered intraperitoneally) and body temperature was maintained with a heat lamp.

Rat pancreatic islets of Langerhans were isolated from the pancreas of 8rats by collagenase P (Boehringer, Meylan, France) digestion. Isletswere purified by sedimentation in Hanks balanced salt solution [NaCl(137 mM); KCl (5.36 mM); MgSO₄, 7 H₂O (0.81 mM); Na₂HPO₄, 12 H₂O (0.34mM); KH₂PO₄ (0.44 mM); CaCl₂, 2 H₂ (1.26 mM) NaHCO₃ (4.17 mM)] followedby Ficoll gradient separation. Islets were then hand-picked understereoscopic microscope and batches of 3 islets were incubated for 90minutes at 37° C. with continuous shaking under a humidified condition(95% O₂, 5% CO₂) in 1 ml of Krebs/Hepes pH 7 solution [NaCl (115 mM),NaHCO₃ (24 mM), KCl (5 mM), MgCl₂ (1 mM), CaCl₂, 2H₂O (1 mM), 0.2% ofBovine serum albumin (Fraction V, fatty acid free, Boehringer,Mannheim), 10 mM Hepes] containing the required glucose or compoundconcentration. Compounds were dissolved in DMSO at 2.10-2M stocksolutions. They were then diluted at the required concentration inKrebs/Hepes buffer containing the required glucose concentration.

At the end of incubation, media was collected and insulin levels weremeasured using ELISA (EUROBIO, Courtaboeuf, France).

TABLE Dose response effect of compounds on insulin secretion in diabeticNOSTZ rat islets. GLUCOSE 2.8 MM GLUCOSE 8 MM COMPOUND (M) 0 10-4 0 10-710-6 10-5 10-4 3 100 ± 9 85 ± 8  100 ± 5 100 ± 7 110 ± 7 145 ± 9 168 ±7  3-7 100 ± 9 84 ± 10 100 ± 9 124 ± 7 149 ± 9 210 ± 9 228 ± 12

Islets were hand-picked and incubated in the presence of increasingconcentrations of compounds in the presence of glucose at 2.8 or 8 mM.At the end of incubation, media was collected and insulin levels weremeasured using ELISA method. Results are expressed as % of glucosecontrol (2.8 or 8 mM) and represent Means±SEM.

In islets isolated from NOSTZ diabetic rats, the compounds showed noeffect in the presence of a low, non-stimulatory, glucose concentration(2.8 mM), even at high concentration (10⁻⁴ M), while they potentiatedinsulin secretion in response to 8 mM glucose, a stimulatory glucoseconcentration. These results show that the effect of the compounds onthe insulin secretion is dependent on the glucose level and suggest thata treatment with these compounds should avoid hypoglycemic risk

1.-24. (canceled)
 25. A compound of the formula (I)

wherein: one atom among Y, Z, W is a nitrogen atom and the other atomsfrom Y, Z and W, and also X, are a carbon atom substituted by asubstituent selected from: hydrogen, or T; A is: aryl, heteroaryl,cycloalkyl, heterocycloalkyl, arylalkyl, aryloxyalkyl, arylalkoxy alkyl,arylthioalkyl, arylalkylthioalkyl, heteroarylalkyl, heteroaryloxyalkyl,heteroarylalkoxyalkyl, heteroarylthioalkyl, heteroarylalkylthioalkyl,heterocycloalkylalkyl, heterocycloalkyloxyalkyl,heterocycloalkylalkoxyalkyl, heterocycloalkylthioalkyl,heterocycloalkylalkylthioalkyl, arylakenyl, or arylalkynyl; theheteroaryl or heterocycloalkyl groups having one or more heteroatomselected from N, O and S; each of these groups optionally substituted byone or more substituents selected from T; R1 is: alkyl, alkyloxyalkyl,cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkyloxyalkyl,heterocycloalkylalkoxyalkyl, heterocycloalkylthioalkyl,heterocycloalkylalkylthioalkyl, R3R4N-alkyl, aryl, heteroaryl,arylalkyl, or heteroarylalkyl; each of these groups optionallysubstituted by one or more substituents selected from T; T is: hydroxy,thio, halogen, cyano, trifluoromethoxy, trifluoromethyl, carboxy,carboxy methyl, carboxyethyl, alkyl, cycloalkyl, alkoxy, alkylamino,aryl, arylsulfonylalkyl, aryloxy, arylalkoxy, NR3R4, azido, nitro,guanidino, amidino, phosphono, oxo, carbamoyl, alkylsulfonyl,alkylsulfinyl, alkylthio, or SF₅, or two T groups together formmethylenedioxy; R3 and R4 are independently selected from: hydrogen,lower alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or R3and R4 together form a heterocycloalkyl group which has one or moreheteroatoms selected from N, O and S; and R3 and R4 are independentlyoptionally substituted by one or more substituents selected from T; aswell as its racemic forms, tautomers, enantiomers, diastereomers,epimers and polymorphs, and mixtures thereof, and the pharmaceuticallyacceptable salts thereof.
 26. A compound according to claim 25, whereinA is aryl, arylalkyl, or heteroaryl with one or more heteroatomsselected from N, O and S; and each of these groups is optionallysubstituted by one or more substituents selected from T.
 27. A compoundaccording to claim 26, wherein A is phenyl or benzyl, and each of thesegroups is optionally substituted by one or more substituents selectedfrom T.
 28. A compound according to claim 25, wherein R1 is alkyl,alkyloxyalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl,heterocycloalkyloxyalkyl, heterocycloalkylalkoxyalkyl,heterocycloalkylthioalkyl, or heterocycloalkylalkylthioalkyl, and eachof these groups is optionally substituted by one or more substituentsselected from T.
 29. A compound according to claim 28, wherein R1 isalkyl, alkyloxyalkyl, cycloalkyl, cycloalkylalkyl; each of these groupscan be optionally substituted by one or more substituents selected fromT.
 30. A compound according to claim 29, wherein R1 is ethyl; isopropyl;butyl; 2,2-difluoroethyl; 2-methoxyethyl; cyclopropyl;cyclopropylmethyl; or cyclobutyl.
 31. A compound according to claim 25,wherein T is hydroxy, thio, halogen, cyano, trifluoromethoxy,trifluoromethyl, carboxy, carboxymethyl, carboxyethyl, alkyl,cycloalkyl, alkoxy, aryl, arylsulfonylalkyl, aryloxy, arylalkoxy, NR3R4,azido, guanidino, amidino, phosphono, oxo, carbamoyl, alkylsulfonyl,alkylsulfinyl, alkylthio, or SF₅, or two T groups together formmethylenedioxy.
 32. A compound according to claim 25, wherein T ishalogen, trifluoromethyl, alkyl, cycloalkyl, or alkoxy.
 33. A compoundaccording to claim 25, wherein T is methyl, cycloalkyl, Cl, or F.
 34. Acompound according to claim 25, wherein R3 and R4 are independentlyselected from lower alkyl and cycloalkyl.
 35. A compound according toclaim 25, selected from the following compounds:1-cyclopropyl-3-(4-fluorophenyl)pyrido[3,4-b]pyrazin-2(1H)-one;1-cyclopropyl-3-[4-(trifluoromethyl)phenyl]pyrido[3,4-b]pyrazin-2(1H)-one;1-cyclopropyl-3-phenylpyrido[3,4-b]pyrazin-2(1H)-one; and3-(4-chlorophenyl)-1-cyclopropylpyrido[3,4-b]pyrazin-2(1H)-one; as wellas its racemic forms, tautomers, enantiomers, diastereomers, epimers andpolymorphs, and mixtures thereof, and the pharmaceutically acceptablesalts thereof.
 36. A process for the preparation of the compounds offormula (I) according to claim 25, the process comprising: a) reacting acompound of formula (I)

wherein: X, Y, Z, W are as defined in claim 1; Hal is a halogen atom;with an amine R1-NH₂, wherein R1 is as defined in claim 1, in thepresence of a base in an inert solvent, to give a compound of formula(2)

b) reducing the compound of formula (2) with a metal or metal in lowerstate of oxidation in acids; or by catalytic hydrogenation with metalcatalysts in solvents, to obtain a compound of formula (3)

c) reacting the compound of formula (3) with an α-keto acid compound ofthe following formula

wherein: A is as defined in claim 1; Rx is Hal, as above defined; orORe, wherein Re is hydrogen, lower alkyl; in a solvent, to obtain acompound of formula (I).
 37. A process for the preparation of thecompounds of formula (I) according to claim 25, the process comprising:a) reacting a compound of formula (I)

wherein: X, Y, Z, W are as defined in claim 1; Hal is a halogen atom;with an amine R1-NH₂, wherein R1 is as defined in claim 1, in thepresence of a base in an inert solvent, to give a compound of formula(2)

d) reducing the compound of formula (2) with a metal or metal in lowerstate of oxidation in acids; or by catalytic hydrogenation with metalcatalysts in solvents, to obtain a compound of formula (3)

e) reacting the compound of formula (3) with a compound of the followingformula

wherein Rx is as above defined, in the presence of a base, in a inertsolvent, to obtain the compound of formula (5);

f) reacting the compound of formula (5) with a brominating agent in aninert solvent, to give the compound of formula (6)

g) reacting the compound of formula (6) with a boronic acid compound oran ester thereof, in the presence of a base and a catalyst in an inertsolvent, to obtain a compound of formula (I).
 38. A method comprisingadministering to a patient a compound of claim 25, or its racemic forms,tautomers, enantiomers, diastereomers, epimers or polymorphs, ormixtures thereof, or pharmaceutically acceptable salts thereof, for thetreatment of a pathology associated with hyperglycaemia.
 39. A methodaccording to claim 38, for treating atherosclerosis or myocardialischemia.
 40. A method according to claim 38, wherein the treatmentinduces insulin secretion in response to glucose concentration.
 41. Amethod according to claim 38 for the treatment of diabetes.
 42. A methodaccording to claim 38 for the treatment of type II diabetes.
 43. Amethod according to claim 38 for the treatment of dyslipidaemia orobesity.
 44. A method according to claim 38 for the treatment ofdiabetes related microvascular or macrovascular complications.
 45. Amethod according to claim 38 for the treatment of arterial hypertension,atherosclerosis, inflammatory processes, microangiopathy,macroangiopathy, retinopathy or neuropathy.
 46. A method according toclaim 38 for reducing hyperglycaemia.
 47. A pharmaceutical compositioncontaining at least a compound of formula (I) according to claim 25 anda pharmaceutically acceptable excipient.
 48. A method comprisingadministering to a patient a compound of formula (I) below, or itsracemic forms, tautomers, enantiomers, diastereomers, epimers orpolymorphs, or mixtures thereof, or pharmaceutically acceptable saltsthereof, for the treatment of a pathology associated withhyperglycaemia, excluding type II diabetes:

wherein: one atom among X, Y, Z, and W is a nitrogen atom and the otheratoms from X, Y, Z and W, are a carbon atom substituted by a substituentselected from: hydrogen, or T; A is: aryl, heteroaryl, cycloalkyl,heterocycloalkyl, arylalkyl, aryloxyalkyl, arylalkoxy alkyl,arylthioalkyl, arylalkylthioalkyl, heteroarylalkyl, heteroaryloxyalkyl,heteroarylalkoxyalkyl, heteroarylthioalkyl, heteroarylalkylthioalkyl,heterocycloalkylalkyl, heterocycloalkyloxyalkyl,heterocycloalkylalkoxyalkyl, heterocycloalkylthioalkyl,heterocycloalkylalkylthioalkyl, arylakenyl, or arylalkynyl; theheteroaryl or heterocycloalkyl groups having one or more heteroatomselected from N, O and S; each of these groups optionally substituted byone or more substituents selected from T; R1 is: alkyl, alkyloxyalkyl,cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkyloxyalkyl,heterocycloalkylalkoxyalkyl, heterocycloalkylthioalkyl,heterocycloalkylalkylthioalkyl, R3R4N-alkyl, aryl, heteroaryl,arylalkyl, or heteroarylalkyl; each of these groups optionallysubstituted by one or more substituents selected from T; T is: hydroxy,thio, halogen, cyano, trifluoromethoxy, trifluoromethyl, carboxy,carboxy methyl, carboxyethyl, alkyl, cycloalkyl, alkoxy, alkylamino,aryl, arylsulfonylalkyl, aryloxy, arylalkoxy, NR3R4, azido, nitro,guanidino, amidino, phosphono, oxo, carbamoyl, alkylsulfonyl,alkylsulfinyl, alkylthio, or SF₅, or two T groups together formmethylenedioxy; R3 and R4 are independently selected from: hydrogen,lower alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or R3and R4 together form a heterocycloalkyl group which has one or moreheteroatoms selected from N, O and S; and R3 and R4 are independentlyoptionally substituted by one or more substituents selected from T; aswell as its racemic forms, tautomers, enantiomers, diastereomers,epimers and polymorphs, and mixtures thereof, and the pharmaceuticallyacceptable salts thereof.
 49. A method according to claim 48, fortreating atherosclerosis or myocardial ischemia.
 50. A method accordingto claim 48, wherein the treatment induces insulin secretion in responseto glucose concentration.
 51. A method according to claim 48 for thetreatment of diabetes.
 52. A method according to claim 48 for thetreatment of dyslipidaemia or obesity.
 53. A method according to claim48 for the treatment of diabetes related microvascular or macrovascularcomplications.
 54. A method according to claim 48 for the treatment ofarterial hypertension, atherosclerosis, inflammatory processes,microangiopathy, macroangiopathy, retinopathy or neuropathy.
 55. Amethod according to claim 48 for reducing hyperglycaemia.
 56. A methodaccording to claim 48, wherein the compound of formula (I) is selectedfrom the following compounds:1-cyclopropyl-3-(4-fluorophenyl)pyrido[3,4-b]pyrazin-2(1H)-one;1-cyclopropyl-3-[4-(trifluoromethyl)phenyl]pyrido[3,4-b]pyrazin-2(1H)-one;1-cyclopropyl-3-phenylpyrido[3,4-b]pyrazin-2(1H)-one;2-(3-chlorophenyl)-4-cyclopropylpyrido[2,3-b]pyrazin-3(4H)-one;2-(4-chloro-2-methylphenyl)-4-cyclopropylpyrido[2,3-b]pyrazin-3(4H)-one;(4-chlorobenzyl)-4-cyclopropylpyrido[2,3-b]pyrazin-3(4H)-one;2-(4-chlorophenyl)-4-(2,2-difluoroethyl)pyrido[2,3-b]pyrazin-3(4H)-one;2-(4-chlorophenyl)-4-(2-methoxyethyl)pyrido[2,3-b]pyrazin-3(4H)-one;2-(4-chlorophenyl)-4-cyclopropyl-6-methylpyrido[2,3-b]pyrazin-3(4H)-one;2-(4-chlorophenyl)-4-cyclopropyl-7-methylpyrido[2,3-b]pyrazin-3(4H)-one;2-(4-chlorophenyl)-4-cyclopropyl-8-methylpyrido[2,3-b]pyrazin-3(4H)-one;2-(4-chlorophenyl)-4-cyclopropylmethylpyrido[2,3-b]pyrazin-3(4H)-one;2-(4-chlorophenyl)-4-cyclopropylpyrido[2,3-b]pyrazin-3(4H)-one;2-(4-chlorophenyl)-4-ethylpyrido[2,3-b]pyrazin-3(4H)-one;2-(4-chlorophenyl)-4-isopropyl-pyrido[2,3-b]pyrazin-3(4H)-one;2-(4-fluorophenyl)-4-(2-methoxyethyl)pyrido[2,3-b]pyrazin-3(4H)-one;2-(4-fluorophenyl)-4-ethylpyrido[2,3-b]pyrazin-3(4H)-one;2-(4-fluorophenyl)-4-isopropyl-pyrido[2,3-b]pyrazin-3(4H)-one;3-(4-chlorophenyl)-1-cyclopropylpyrido[3,4-b]pyrazin-2(1H)-one;4-(2,2-difluoroethyl)-2-(4-fluorophenyl)pyrido[2,3-b]pyrazin-3(4H)-one;4-(2,2-difluoroethyl)-2-(4-trifluoromethylphenyl)pyrido[2,3-b]pyrazin-3(4H)-one;4-(2,2-difluoroethyl)-2-phenylpyrido[2,3-b]pyrazin-3(4H)-one;4-(2-methoxyethyl)-2-(4-trifluoromethylphenyl)-pyrido[2,3-b]pyrazin-3(4H)-one;4-(2-methoxyethyl)-2-phenylpyrido[2,3-b]pyrazin-3(4H)-one;4-(cyclopropylmethyl)-2-(4-fluoro-2-methylphenyl)pyrido[2,3-b]pyrazin-3(4H)-one;4-butyl-2-(4-chlorophenyl)-pyrido[2,3-b]pyrazin-3(4H)-one;4-cyclobutyl-2-(4-fluorophenyl)pyrido[2,3-b]pyrazin-3(4H)-one;4-cyclopropyl-2-(3-fluorophenyl)-pyrido[2,3-b]pyrazin-3(4H)-one;4-cyclopropyl-2-(3-methylphenyl)pyrido[2,3-b]pyrazin-3(4H)-one;4-cyclopropyl-2-(4-fluoro-2-methylphenyl)pyrido[2,3-b]pyrazin-3(4H)-one;4-cyclopropyl-2-(4-fluoro-2-methylphenyl)pyrido[2,3-b]pyrazin-3(4H)-one;4-cyclopropyl-2-(4-fluorophenyl)-6-methoxypyrido[2,3-b]pyrazin-3(4H)-one;4-cyclopropyl-2-(4-fluorophenyl)-6-methylpyrido[2,3-b]pyrazin-3(4H)-one;4-cyclopropyl-2-(4-fluorophenyl)-7-methylpyrido[2,3-b]pyrazin-3(4H)-one;4-cyclopropyl-2-(4-fluorophenyl)-8-methylpyrido[2,3-b]pyrazin-3(4H)-one;4-cyclopropyl-2-(4-fluorophenyl)pyrido[2,3-b]pyrazin-3(4H)-one;4-cyclopropyl-2-(4-methylphenyl)pyrido[2,3-b]pyrazin-3(4H)-one;4-cyclopropyl-2-(4-trifluoromethylphenyl)-8-methylpyrido[2,3-b]pyrazin-3(4H)-one;4-cyclopropyl-2-(4-trifluoromethylphenyl)-8-methylpyrido[2,3-b]pyrazin-3(4H)-one;4-cyclopropyl-2-(4-trifluoromethylphenyl)-pyrido[2,3-b]pyrazin-3(4H)-one;4-cyclopropyl-2-[3-(trifluoromethyl)phenyl]pyrido[2,3-b]pyrazin-3(4H)-one;4-cyclopropyl-2-phenylpyrido[2,3-b]pyrazin-3(4H)-one;4-cyclopropylmethyl-2-(4-fluoro-2-methylphenyl)-pyrido[2,3-b]pyrazin-3(4H)-one;4-cyclopropylmethyl-2-(4-fluorophenyl)pyrido[2,3-b]pyrazin-3(4H)-one;4-cyclopropylmethyl-2-(4-trifluoromethylphenyl)pyrido[2,3-b]pyrazin-3(4H)-one;4-cyclopropylmethyl-2-phenylpyrido[2,3-b]pyrazin-3(4H)-one;4-ethyl-2-phenylpyrido[2,3-b]pyrazin-3(4H)-one;4-isopropyl-2-phenylpyrido[2,3-b]pyrazin-3(4H)-one,2-(2-Chlorophenyl)-4-cyclopropylpyrido[2,3-b]pyrazin-3(4H)-one;4-Cyclopropyl-2-(2,4-dichlorophenyl)pyrido[2,3-b]pyrazin-3(4H)-one;4-Cyclopropyl-2-(2,4,5-trifluorophenyl)pyrido[2,3-b]pyrazin-3(4H)-one;4-Cyclopropyl-2-(2-methoxyphenyl)pyrido[2,3-b]pyrazin-3(4H)-one;4-Cyclopropyl-2-(4-methoxyphenyl)pyrido[2,3-b]pyrazin-3(4H)-one;2-(4-Chloro-2-methylphenyl)-4-isopropylpyrido[2,3-b]pyrazin-3(4H)-one;2-(2,4-Dichlorophenyl)-4-isopropylpyrido[2,3-b]pyrazin-3(4H)-one;2-(4-Fluoro-2-methylphenyl)-4-isopropylpyrido[2,3-b]pyrazin-3(4H)-one;2-(2-Ethoxyphenyl)-4-isopropylpyrido[2,3-b]pyrazin-3(4H)-one;4-cyclopropyl-2-(6-methoxypyridin-3-yl)pyrido[2,3-b]pyrazin-3(4H)-one;4-cyclopropyl-2-(2-thienyl)pyrido[2,3-b]pyrazin-3(4H)-one;4-cyclopropyl-2-(2-furyl)pyrido[2,3-b]pyrazin-3(4H)-one;2-(4-Chlorophenyl)-4-(2-hydroxyethyl)pyrido[2,3-b]pyrazin-3(4H)-one;2-(4-Fluorophenyl)-4-(2-hydroxyethyl)pyrido[2,3-b]pyrazin-3(4H)-one;4-(2-hydroxyethyl)-2-phenylpyrido[2,3-b]pyrazin-3(4H)-one;2-(4-Chlorophenyl)-4-(3-hydroxypropyl)pyrido[2,3-b]pyrazin-3(4H)-one;2-(4-Fluorophenyl)-4-(3-hydroxypropyl)pyrido[2,3-b]pyrazin-3(4H)-one;4-(3-Hydroxypropyl)-2-phenylpyrido[2,3-b]pyrazin-3(4H)-one;2-(4-chloro-2-methylphenyl)-4-(2-hydroxyethyl)pyrido[2,3-b]pyrazin-3(4H)-one;2-(4-fluoro-2-methylphenyl)-4-(2-hydroxyethyl)pyrido[2,3-b]pyrazin-3(4H)-one;2-(4-chloro-2-methylphenyl)-4-(2-methoxyethyl)pyrido[2,3-b]pyrazin-3(4H)-one;2-(4-fluoro-2-methylphenyl)-4-(2-methoxyethyl)pyrido[2,3-b]pyrazin-3(4H)-one;4-cyclopropyl-2-(2,4-dimethylphenyl)pyrido[2,3-b]pyrazin-3(4H)-one;2-(4-chlorophenyl)-4-[2-(diethylamino)ethyl]pyrido[2,3-b]pyrazin-3(4H)-one;2-(4-chlorophenyl)-4-[2-(diethylamino)ethyl]pyrido[2,3-b]pyrazin-3(4H)-one;and 1-ethyl-3-(4-fluorophenyl)pyrido[2,3-b]pyrazin-2(1H)-one; as well asits racemic forms, tautomers, enantiomers, diastereomers, epimers andpolymorphs, and mixtures thereof, and the pharmaceutically acceptablesalts thereof.
 57. A method according to claim 48, wherein the compoundof formula (I) is selected from the following compounds:2-(4-chlorobenzyl)-4-cyclopropylpyrido[2,3-b]pyrazin-3(4H)-one;2-(4-chlorophenyl)-4-(2,2-difluoroethyl)pyrido[2,3-b]pyrazin-3(4H)-one;2-(4-chlorophenyl)-4-(cyclopropylmethyl)pyrido[2,3-b]pyrazin-3(4H)-one;2-(4-chlorophenyl)-4-cyclopropylmethylpyrido[2,3-b]pyrazin-3(4H)-one;2-(4-chlorophenyl)-4-cyclopropylpyrido[2,3-b]pyrazin-3(4H)-one;2-(4-chlorophenyl)-4-ethylpyrido[2,3-b]pyrazin-3(4H)-one;2-(4-chlorophenyl)-4-isopropyl-pyrido[2,3-b]pyrazin-3(4H)-one;2-(4-fluorophenyl)-4-(2-methoxyethyl)pyrido[2,3-b]pyrazin-3(4H)-one;2-(4-fluorophenyl)-4-(2-methoxyethylpyrido[2,3-b]pyrazin-3(4H)-one;2-(4-fluorophenyl)-4-ethylpyrido[2,3-b]pyrazin-3(4H)-one;2-(4-Fluorophenyl)-4-(2-hydroxyethyl)pyrido[2,3-b]pyrazin-3(4H)-one;4-cyclopropyl-2-(4-fluorophenyl)pyrido[2,3-b]pyrazin-3(4H)-one;4-cyclopropyl-2-ethylpyrido[2,3-b]pyrazin-3(4H)-one;4-cyclopropylmethyl-2-(4-fluorophenyl)pyrido[2,3-b]pyrazin-3(4H)-one;4-ethyl-2-phenylpyrido[2,3-b]pyrazin-3(4H)-one; as well as its racemicforms, tautomers, enantiomers, diastereomers, epimers and polymorphs,and mixtures thereof, and the pharmaceutically acceptable salts thereof.